Coagulation Factor Xa inhibits cancer cell migration via LIMK1-mediated cofilin inactivation

Keren Borensztajn; Maikel P. Peppelenbosch; C. Arnold Spek

doi:10.1016/j.thromres.2010.02.018

Coagulation Factor Xa inhibits cancer cell migration via LIMK1-mediated cofilin inactivation

Keren Borensztajn^*
, Maikel P. Peppelenbosch
, C. Arnold Spek

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

28 Citations (Scopus)

Abstract

Previously, we showed that activated coagulation factor X (FXa) inhibits migration of breast, lung and colon cancer cells. We showed that the effect of FXa on migration was protease-activated receptor (PAR)-1-dependent, but the subsequent cellular signaling routes remained elusive. In the current manuscript, we show that both the Rho/ROCK and Src/FAK/paxillin pathways are required for FXa-mediated inhibition of breast cancer cell migration. FXa induced pronounced stress fiber formation that was partially inhibited by pre-treatment with specific ROCK or Src inhibitors. Downstream of Rho/ROCK and Src/FAK/paxillin, FXa induced myosin light chain phosphorylation and LIMK1 activation resulting in cofilin inactivation. Knocking-down LIMK1 expression abolished FXa-induced inhibition of cell invasion. Our results reveal that FXa-mediated sustained cofilin inactivation leads to stabilization of actin. laments incompatible with migration. Overall we confirm that, beyond its role in blood coagulation, FXa plays a key role in cell migration and we unravel a new mechanism of PAR-1-mediated inhibition of migration via Rho and Src dependent pathways. (C) 2010 Elsevier Ltd. All rights reserved.

Original language	English
Pages (from-to)	E323-E328
Number of pages	6
Journal	Thrombosis Research
Volume	125
Issue number	6
DOIs	https://doi.org/10.1016/j.thromres.2010.02.018
Publication status	Published - Jun-2010

Keywords

Coagulation factor Xa
Cancer cell
Cell migration
Protease activated receptor
Signaling
MEDIATED TYROSINE PHOSPHORYLATION
PROTEASE-ACTIVATED RECEPTOR-2
FOCAL ADHESION KINASE
TUMOR-CELLS
SPHINGOSINE 1-PHOSPHATE
DIFFERENTIAL REGULATION
COUPLED RECEPTOR
CARCINOMA CELLS
FACTOR-VIIA
LIM KINASE

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@article{8a960cb4e3964233a151e878a43e89be,

title = "Coagulation Factor Xa inhibits cancer cell migration via LIMK1-mediated cofilin inactivation",

abstract = "Previously, we showed that activated coagulation factor X (FXa) inhibits migration of breast, lung and colon cancer cells. We showed that the effect of FXa on migration was protease-activated receptor (PAR)-1-dependent, but the subsequent cellular signaling routes remained elusive. In the current manuscript, we show that both the Rho/ROCK and Src/FAK/paxillin pathways are required for FXa-mediated inhibition of breast cancer cell migration. FXa induced pronounced stress fiber formation that was partially inhibited by pre-treatment with specific ROCK or Src inhibitors. Downstream of Rho/ROCK and Src/FAK/paxillin, FXa induced myosin light chain phosphorylation and LIMK1 activation resulting in cofilin inactivation. Knocking-down LIMK1 expression abolished FXa-induced inhibition of cell invasion. Our results reveal that FXa-mediated sustained cofilin inactivation leads to stabilization of actin. laments incompatible with migration. Overall we confirm that, beyond its role in blood coagulation, FXa plays a key role in cell migration and we unravel a new mechanism of PAR-1-mediated inhibition of migration via Rho and Src dependent pathways. (C) 2010 Elsevier Ltd. All rights reserved.",

keywords = "Coagulation factor Xa, Cancer cell, Cell migration, Protease activated receptor, Signaling, MEDIATED TYROSINE PHOSPHORYLATION, PROTEASE-ACTIVATED RECEPTOR-2, FOCAL ADHESION KINASE, TUMOR-CELLS, SPHINGOSINE 1-PHOSPHATE, DIFFERENTIAL REGULATION, COUPLED RECEPTOR, CARCINOMA CELLS, FACTOR-VIIA, LIM KINASE",

author = "Keren Borensztajn and Peppelenbosch, \{Maikel P.\} and Spek, \{C. Arnold\}",

year = "2010",

month = jun,

doi = "10.1016/j.thromres.2010.02.018",

language = "English",

volume = "125",

pages = "E323--E328",

journal = "Thrombosis Research",

issn = "0049-3848",

publisher = "PERGAMON-ELSEVIER SCIENCE LTD",

number = "6",

}

TY - JOUR

T1 - Coagulation Factor Xa inhibits cancer cell migration via LIMK1-mediated cofilin inactivation

AU - Borensztajn, Keren

AU - Peppelenbosch, Maikel P.

AU - Spek, C. Arnold

PY - 2010/6

Y1 - 2010/6

N2 - Previously, we showed that activated coagulation factor X (FXa) inhibits migration of breast, lung and colon cancer cells. We showed that the effect of FXa on migration was protease-activated receptor (PAR)-1-dependent, but the subsequent cellular signaling routes remained elusive. In the current manuscript, we show that both the Rho/ROCK and Src/FAK/paxillin pathways are required for FXa-mediated inhibition of breast cancer cell migration. FXa induced pronounced stress fiber formation that was partially inhibited by pre-treatment with specific ROCK or Src inhibitors. Downstream of Rho/ROCK and Src/FAK/paxillin, FXa induced myosin light chain phosphorylation and LIMK1 activation resulting in cofilin inactivation. Knocking-down LIMK1 expression abolished FXa-induced inhibition of cell invasion. Our results reveal that FXa-mediated sustained cofilin inactivation leads to stabilization of actin. laments incompatible with migration. Overall we confirm that, beyond its role in blood coagulation, FXa plays a key role in cell migration and we unravel a new mechanism of PAR-1-mediated inhibition of migration via Rho and Src dependent pathways. (C) 2010 Elsevier Ltd. All rights reserved.

AB - Previously, we showed that activated coagulation factor X (FXa) inhibits migration of breast, lung and colon cancer cells. We showed that the effect of FXa on migration was protease-activated receptor (PAR)-1-dependent, but the subsequent cellular signaling routes remained elusive. In the current manuscript, we show that both the Rho/ROCK and Src/FAK/paxillin pathways are required for FXa-mediated inhibition of breast cancer cell migration. FXa induced pronounced stress fiber formation that was partially inhibited by pre-treatment with specific ROCK or Src inhibitors. Downstream of Rho/ROCK and Src/FAK/paxillin, FXa induced myosin light chain phosphorylation and LIMK1 activation resulting in cofilin inactivation. Knocking-down LIMK1 expression abolished FXa-induced inhibition of cell invasion. Our results reveal that FXa-mediated sustained cofilin inactivation leads to stabilization of actin. laments incompatible with migration. Overall we confirm that, beyond its role in blood coagulation, FXa plays a key role in cell migration and we unravel a new mechanism of PAR-1-mediated inhibition of migration via Rho and Src dependent pathways. (C) 2010 Elsevier Ltd. All rights reserved.

KW - Coagulation factor Xa

KW - Cancer cell

KW - Cell migration

KW - Protease activated receptor

KW - Signaling

KW - MEDIATED TYROSINE PHOSPHORYLATION

KW - PROTEASE-ACTIVATED RECEPTOR-2

KW - FOCAL ADHESION KINASE

KW - TUMOR-CELLS

KW - SPHINGOSINE 1-PHOSPHATE

KW - DIFFERENTIAL REGULATION

KW - COUPLED RECEPTOR

KW - CARCINOMA CELLS

KW - FACTOR-VIIA

KW - LIM KINASE

U2 - 10.1016/j.thromres.2010.02.018

DO - 10.1016/j.thromres.2010.02.018

M3 - Article

SN - 0049-3848

VL - 125

SP - E323-E328

JO - Thrombosis Research

JF - Thrombosis Research

IS - 6

ER -

Coagulation Factor Xa inhibits cancer cell migration via LIMK1-mediated cofilin inactivation

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Keywords

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